Treatment of depressed states



United States Patent 3,360,435 TREATMENT OF DEPRESSED STATES AlexanderKandel and Paul Merrill Lish, Evansville, Ind., assignors to MeadJohnson & Company, Evansville, Ind., a corporation of Indiana NoDrawing. Filed May 21, 1965, Ser. No. 457,837 5 Claims. (Cl. 16765) Thepresent invention concerns a method for controlling depression. Thisapplication is a continuation-inpart of the copending application Ser.No. 397,673, filed Sept. 15, 1964, now abandoned.

It has been found that antidepressant effects are elicited when 1(Z-dimethylaminoethyl) l-phenylindene, 1-[2-(methylamino)ethyl]-1-phenylindene, or a pharmaceutically acceptableacid addition salt thereof is administered to a host subject to adepressed condition.

Important advances in the treatment of mentally disturbed patients ofthe excited type through the use of central nervous system depressantcompounds, commonly referred to as tranquilizers, have been made. At theopposite end of the spectrum of psychotic states are the depressed orrepressed subjects for whom treatment with stimulant drugs or varioustypes of shock treatment has been used. More recently certain drugswhich are known as antidepressants have come into use for treatment ofthe latter conditions. These drugs are characterized by an ability torelieve the depression of such subjects, although they exert nostimulating effect on the alertness, mood, or activity of normalsubjects in contrast to the well-known psychostimulants, such asamphetamine, caffeine, or the analeptic drugs. Psychostimulantscharacteristically increase the blood pressure and reduce the appetite,while the new class of antidepressant substances frequently have justthe reverse effect.

The measurement of antidepressant effects in the laboratory isaccomplished by means of a group of tests referred to generally asreserpine antagonism tests. One of the effects of reserpine on which itspharmacologic use is based is its ability to induce a depressed state.In the mouse, concomitant pharmacologic or physiologic effects areexerted, including hypothermia, ptosis, and miosis. Antidepressantdrugs, such as imipramine and amitriptyline have the capacity to preventthese physiological effects.

In one such test, a predetermined dose of test compound is administeredorally to each mouse of several groups of test mice. One hour laterreserpine, 2.0 mg./kg., is injected intravenously, and one hourfollowing the reserpine dose ptosis is measured by placing each mouse ona platform away from light and estimating the extent of closure of thepalpebral fissure. Ptosis is significant if the opening is not greaterthan 50% of normal. The reserpine effect is significantly modified ifthe palpebral opening is greater than 50% of normal. In a similar testthe reduction of rectal temperature following reserpine is used as aparameter. Reserpine alone produces a significant reduction of rectaltemperature in mice. Antidepresant drugs will prevent this effect.

Antidepressant drugs can be distinguished from psychostimulan-t drugssuch as amphetamine by reversing the order of administration in theabove test. That is, by administering reserpine first followed by thetest drug, the extent of reversal of reserpine effect can be determined.Psychostimulants characteristically have the ability to reverse thereserpine effects, while the antidepressants do not. That is, theantidepressants will prevent but not reverse the reserpiue effects inmice.

The above tests are conducted according to accepted pharmacologicaltechnique, by administering various doses of drug-s to groups of testanimals and then conexhibits an ED value of 10 mg./-kg., whileI-(Z-dimethylaminoethyl) l-phenylindene hydrochloride exhibits ED valuefor the prevention of reserpine ptosis in mice administration ofI-(Z-dimethylaminoethyl) l-phenylindene hydrochloride elicits a trulyoutstanding antireserpine effect in animals characterizing the materialas an antidepressant agent.

PREPARATION 1-(2-dimethylaminoethyl) l-phenylindene is prepared from3-phenylindene by alkylation thereof with a 2-dimethylaminoethyl halidesuch as the bromide, chloride or iodide or other alkylating agentcapable of introducing the Z-dime-thylaminoethyl group. An example ofsuch other alkylating agent is a reactive ester ofZ-dimethylaminoethanol such as the ester with p-toluenesulfonic acid.The alkylation of 3-phenylindene with a Z-dimethylaminoethyl halide orother reactive ester of Z-dimethylaminoethanol is conducted on an alkalimetal salt of3- phenylindene. The intermediate alkali metal salt isprepared by reaction of 3-phenylindene with a strong base such as sodiumamide, sodium hydride, lithium amide, butyl lithium, sodiumtriphenylmethyl, or others. The alkali metal salt of 3-phenylindene ispreferably prepared in situ and allowed to react with theZ-dimethylaminoethyl halide without isolation. For this reason, thealkali metal base employed for salt formation may be looked upon simplyas a condensing agent for the reaction between 3-phenylindene andZ-dimethylarninoethyl halide.

There results from this reaction a mixture of isomeric products as isshown by the following equation.

(ion.

CH10H:N( Ha):

C5 5 CHaCH2N(CHa)a 0H6 I II Under some reaction conditions, the mixturemay contain dialkylated products as well. This mixture of products canbe separated by conventional methods, including distillation andfractional crystallization of acid addition salts thereof fromappropriate solvents and solvent mixtures. The individal pure productscan then be unequivocally identified by interpretation of their nuclearmagnetic resonance spectra. It has been found that the high degree ofantireserpine activity referred to above is unique to bothI-(Z-dimethylaminoethyl) l-phenylindene,1-[2-(methylamino)ethyl]-1-phenylindene and their salts as distinguishedfrom l-(2-dimethylaminoethyl)-3 phenylindene, the latter substancehaving been found to be essentially inactive in the antagonism ofreserpine ptosisin the mouse.

Compound I is one of the active agents used in the antidepressantprocess of the present invention. Compound II is substantially inactive.Compound II may exist as an isomer or mixture of isomers where thedouble bond is in either the 1,2-position or in the 2,3-position, as isindicated by the dotted line and double headed arrow in the aboveformula.

PROCEDURE 3-phenylindene, 76.8 g., is dissolved in 150 ml. of ether andtreated with 0.4 mole of freshly prepared butyl lithium solution whileprotected from atmospheric moisture by dry nitrogen gas. A temperatureof 20-30" C. is maintained during the addition of the butyl lithiumsolution, after which the solution is refluxed for /2 hour. The reactionmixture is then diluted with 200 ml. of ether and added to a solution of0.5 mole of fl-dimethylaminoethyl chloride in 100 ml. of ether. Afurther reflux period of 2 hours is then commenced, after which thereaction mixture is allowed to cool and then extracted with 200 ml. of6N-hydrochloric acid. The aqueous layer is separated, basified, andextracted with ether. The ether extracts are dried, the solvent removedby distillation, and the residue distilled in vacuo, B.P. l54163/0.2mm., 11 1.5906,

' yield, 56.7 g. This material, 1-(2-dimethylaminoethyl)-1-phenylindene, contaminated with a minor amount of 1-(Z-dimethylaminoethyl)-3-phenylindene, is then dissolved in 850 ml. ofether and treated with anhydrous hydrogen chloride to precipitate thehydrochloride salts. The precipitate is collected by filtration and pure1-(2-dimethylaminoethyl)-3-phenylindene hydrochloride is obtained byrecrystallization thereof from n-propanol (5 ml./g.), M.P. 198-199 C.

AnaIysis.-C, 76.23; H, 7.28.

The nuclear magnetic resonance spectrum measured on a deuterium oxidesolution of the pure sample of 1-(2- dimethylaminoethyl)-l phenylindenehydrochloride described in the preceding paragraph with sodium3-(trimethylsilyl)-1-propanesulfonate as reference using a Varian A60NMR Spectrometer operating at 60 mo. revealed the following: A pair ofdoublets at 6.87 and 6.54 ppm, J=5.7 cps., relative area 2 correspondingto the two vinyl protons; aromatic proton peaks at 7.0 to 7.55 p.p.m.,relative area 9; and aliphatic proton peaks at 2.2 to 2.9 ppm, relativearea 10. The foregoing observations are consistent with the identity ofthe product as having the structure designated by the name1-(2-d-imethylaminoethyl)-l-phenylindene The pure free base1-(Z-dimethylaminoethyl)-1-phenylindene may be obtained by treatment ofthe pure hydrochloride salt having the physical constants listed abovewith a solution of a strong alkali such as aqueous sodium hydroxide. Thepure free base obtained in this fashion has the following properties:

B.P. 147-148/0.7 mm., r1 1.5880. Infrared absorption maxima (film of.pure substance): 698, 732, 755, 775, 790, 1040, 1470, 1615, 2550, and2590 cum- The free base is soluble in the common organic solvents suchas ethanol ether, and benzene.

Any desired pharmaceutically acceptable acid addition salt may beobtained by direct neutralization of the free base with the appropriateacid. Purification of the free base to the extent referred to above isnot necessary for this purpose. If a crude form of the base is employed,care should be taken to characterize the salt formed therefrom, forinstance, by nuclear magnetic resonance studies, as having the structureof Compound I.

Pharmaceutically acceptable acid addition salts are those in which theanion does not contribute significant toxicity to the salt in thedosages thereof employed in accordance with the present invention.Examples of suitable salts are the acetate, propionate, butyrate,pamoate, tannate, mucate, citrate, malate, tosylate, mesylate phosphate,nitrate, sulfate, hydrobromide, hydroiodide, hydrochloride, etc.

The hydrochloride salt described above is soluble in water at roomtemperature to the extent of by weight. It is also soluble in ethanoland in warm isopropanel from which it crystallizes on cooling. It isstable in aqueous solution.

The 1-[2-(methylamino)ethyl] 1 phenylindene may be prepared fromCompound I by demethylation with alkyl haloformate followed byhydrolysis and decarboxylation as shown in the following equation:

X C 02R: Compound I OH; C l-I CHzCHz-N Hydrolysis de :arboxylation 0 H;CHzCHzN C H; VI

where X is chloro, bromo or iodo and R is lower alkyl containing up to 6carbon atoms. The demethylation step proceeds best at temperatures offrom to 150 C. Alternatively the 1-[2-(methylamino)ethyl]-l-phenylindene may be prepared by reacting the l-phenyl indene salt with aN-(2-haloethyl)-N-rnethyl carbamic acid ester of the formula where X andR are as above defined to produce Compound III directly as above shown.The further steps of hydrolysis and decarboxylation are as in the aboveequation and in the procedure following.

The following example illustrates the preparation of Compound IV:

EXAMPLE 1- [Z-(methylamino) ethyl] -1-phenylindene hydrochloride1-(Z-dimethylaminoethyl)-1-phenylindene, 8.8 g. (0.033 mole) isdissolved in 15 ml. of anhydrous benzene and treated cautiously with asolution of 10.9 g. (0.1 mole) of ethyl chloroformate dissolved in 9 ml.of benzene. A vigorous reaction ensues. After the reaction subsides themixture is heated at reflux for 6 hours, diluted with an approximatelyequal volume of benzene, and washed with two 15 ml. portions of dilutehydrochloric acid. The benzene layer is then dried over potassiumcarbonate, the drying agent removed, and the solvent evaporated invacuo. The residual 1-[2-(N-carbethoxy-N-methyl)aminoethyl1-1-phenylindene is then refluxed for 10 hours with a solutionof 6 g. of potassium hydroxide in 25 ml. of aqueous ethanol. Thereaction mixture is cooled, diluted with benzene, and extracted withthree 5 ml. portions of water. The mixture is dried over potassiumcarbonate, and the product recovered from the extract by evaporation asbefore. The residue is dissolved in ether and treated with hydrogenchloride, resulting in precipitation of the desired product. Thismaterial is recrystallized first from an ethylacetate-acetonitrilemixture, and then from acetone, M.P. 176-178 C.

Analysis.Calcd. for C H N-HCl: C, 75.64; H, 7.05; CI. 12.41. Found: C,75.87; H, 7.14; Cl, 12.27.

Infrared absorption maxima are observed at the following wave lengths:3030; 2930; 2760; 2428; 1588; 8; 790, 769, 754, 732 and 699 cmf DOSAGEToxicity studies were conducted in mice of the Swiss- W ebster strainweighing 18 to 25 g. and treated orally with 10 mL/kg. of body weight ofan aqueous solution 75 containing varying doses of1-(Z-dimethylaminoethyl)-1- phenyl-l-indene hydrochloride at a pH of4.0-5.5 by intubation. The animals were observed for signs of sideeffects and the number of deaths occurring within 24 hours was recorded.Dose response curves Were prepared. The dose eliciting detectable sideeffect in 50% of the animals (TD was found to be 14 mg./kg. and the doseresulting in death of 50% of the animals (LD was found to be 84 mg./ kg.Side effects observed included hype activity, increased respiratorydepth, and ataxia. The fact that the effective antidepressant dose(anti-reserpine) is 3.8 mg./ kg. with signs of side effects occurring atonly substantially higher doses, but yet at a dose substantially belowthe lethal level, indicates a wide margin of safety.

The intraperitonea l LD in the mouse is 52.5 mg./kg. The oral LD in therat is 385 mg./kg. The intravenous LD in the dog is estimated to beabout 30 mg./kg.

The effective antidepressant dosage range for l-(2-dimethylaminoethyl) 1phenylindene hydrochloride and l- [2- (methylamino) ethyl]-1-phenylindene hydrochloride in the process of the present invention isfrom about 0.1 mg. to about 5 mg./kg. of body weight of the animal beingtreated. In this dosage range no side effects such as mydriasis, lack ofsalivation, or other side effects which are frequently manifested by thesecondary pharmacologic properties of prior antidepressant drugs areobserved. Dosage according to the present invention may be by either theoral or parenteral routes. In the ordinary case, the oral route ispreferred as a matter of convenience, but occasionally when this methodof dosage cannot be accomplished due to idiosyncrasy, parenteraladministration is satisfactory and preferred.

For human use, a daily dose in the range of to 300 mg. is recommended.Formulations of the following type are satisfactory for this purpose:

Solution for injection.- A sterile aqueous solution having aconcentration of 25 mg./m1. of l-(2-dimethylaminoethyl)-1-phenylindenehydrochloride is prepared by dissolving 25 g. of the substance in 9 l.of water for injection, U.S.P., adjusting to pH 5.5 with dilute aqueoussodium hydroxide, and dilution to 10 1. This solution is then filteredsparkling clear and filled into 2 ml. glass ampoules and sealed. Theampoules are then sterilized by heating.

Capsules-A dry blend of 5.0 g. of1-(2-dimethylaminoethyl)-1-phenylindene hydrochloride, 19.8 g. oflactose, and 0.2 g. of magnesium stearate is prepared. This mixture isthen employed to fill No. 2 hard gelatin capsules, each with 250 mg. ofthe blend.

While several particular embodiments of this invention are shown above,it will be understood, of course, that the invention is not to belimited thereto, since many modifications may be made, and it iscontemplated, therefore, by the appended claims, to cover any suchmodifications as fall within the spirit and scope of this invention.

What is claimed is:

1. The process of eliciting an antidepressant effect in a host subjectto a depressed condition which comprises administering to said host adose of from 0.1 to 5 rug/kg. of body weight of said host of a compoundselected from the group consisting ofl-(2-dimethylaminoethyl)-1-phenylindene, 1-[2-(methyla1mino)ethyl]-1-pbenylidene and the pharmaceutically acceptable acid addition saltsthereof.

2. The process of claim 1 comprising the administration of1-[2-(methylamino)ethyl]-1-phenylindene.

3. The process of claim 1 comprising the administra tion of1-[2-(methylamino)ethyH-I-phenylindene hydrochloride.

4. The process of claim 1 comprising the administration of1-[Z-(methylamino)ethyl]-1-phenylindene.

5. The process of claim 1 comprising the administration of1-[2-(methylamino)ethyl]-1-phenylindene hydrochloride.

References Cited FOREIGN PATENTS 959,704 6/1964 Great Britain.

ALBERT T. MEYERS, Primary Examiner.

JULIAN s. LEVITT, Examiner.

S. FRIEDMAN, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,360,435 December 26, 1967 Alexander Kandel et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, line 13, for "value for the prevention of reserpine ptosis inmice" read of 7.5 mg./kg. It is evident, therefore, that the column 6,lines 23 and 25, for "l- [2- (methy1amino)ethyl]", each occurrence readI-(Z-dimethylaminoethyl) Signed and sealed this 11th day of February1969.

(SEAL) Attest: Edward M. Fletcher, 11'. EDWARD J. BRENNER AttestingOfficer Commissioner of Patents

1. THE PROCESS OF ELICITING AN ANTIDEPRESSANT EFFECT IN A HOST SUBJECTTO A DEPRESSED CONDITION WHICH COMPRISES ADMINISTERING TO SAID HOST ADOSE OF FROM 0.1 TO 5 MG./KG. OF BODY WEIGHT OF SAID HOST OF A COMPOUNDSELECTED FROM THE GROUP CONSISTING OF1-(2-DIMETHYLAMINOETHYL)-1-PHENYLINDENE, 1-(2-(METHYLALMINO)ETHYL) - 1 -PHENYLIDENE AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTSTHEREOF.